Japanese Patent No. 3209946 (Patent Document 1) discloses compounds having neuraminidase inhibitory activity, which include the compound represented by formula (I) shown below. The compound represented by formula (I) has excellent neuraminidase inhibitory activity and is expected to be useful as a drug for treating and preventing influenza virus infections. Japanese Patent No. 4205314 (Patent Document 2) discloses that a certain concentration of the compound represented by formula (I) can be maintained over a long time in respiratory tissues such as the lung (Patent Document 2).
The compound represented by formula (I) can produce the effect of treating/preventing influenza virus infections when administered to the respiratory system of a subject and allowed to remain in the respiratory tissues (such as the upper airway and the lung) of the subject. Therefore, the compound represented by formula (I) needs to be administered not through oral absorption but by using a dosage method and a dosage form which can deliver it to the respiratory tissues through a parenteral route.
An inhalant is a dosage form capable of being administered through a parenteral route. Examples of inhalants include a pressurized metered-dose inhalant which contains a drug dispersed in a pressurized liquefied propellant so that it can be released to atmospheric pressure and inhaled; and a dry powder inhalant. However, pressurized metered-dose inhalants, in which chlorofluorocarbon was used as a propellant, were rapidly replaced by dry powder inhalants during the 1990s, due to regulations against the use of chlorofluorocarbons and the high greenhouse effect of chlorofluorocarbon substitutes on the environment. For example, a dry powder inhalant includes zanamivir (trade name: Relenza) (Patent Document 3), which is an anti-influenza drug having neuraminidase inhibitory activity like the dry powder pharmaceutical composition of the present invention.
Specifically, dry powder inhalants consist of a powder formulation to be inhaled and a device for inhalation. The powder formulation is stored in a container such as a capsule, a blister, or a reservoir or dosing disk in a device, from which a single dose of the powder is inhaled by indrawn breath of the subject. It is reported that the size of particles capable of reaching the respiratory tissues of subjects is approximately 2 to 4 μm (Non-Patent Document 1). It is also reported that there is a correlation between the amount of a drug having a particle size of 4.7 μm or less (fine particle dose) and the amount of the drug that reaches the lung (Non-Patent Document 2). Therefore, the drugs for dry powder inhalants have to be microparticulated.
However, such a microparticulated drug has a problem in that it has a low fluidity by itself and is difficult to handle in the process of manufacturing a preparation. Such a microparticulated drug also clings to the device and may cause a problem of low sprayability.
For these problems, three improving methods have been known. One is a method of adding, to a microparticulated drug, a carrier having a particle size of 30 to 300 μm which is larger than that of the microparticulated drug so that problems with the fluidity and clinging properties of the microparticulated drug can be improved. Lactose, glucose or the like are used as the carrier. A part of the surface of particles of lactose, glucose or the like has high surface energy, and the microparticulated drug deposited on such a part is less likely to separate from the carrier. Therefore, when lactose, glucose or the like is used as the carrier, a manufacturing method (mixing-to-order method) that includes first coating the high surface energy part with fine particles and then mixing a microparticulated drug therewith is used (Non-Patent Documents 3 and 4).
Another is a method in which fine drug particles themselves or a mixture of fine drug particles and carrier particles with the same particle size are formed into loosely bound aggregates with a larger particle size.
The other is a method of forming the drug as porous particles with a high porosity based on the principle that porous particles have an aerodynamic particle size smaller than the geometric particle size. A case is reported in which porous particles show an ability to reach the lung during inhalation, which is comparable to that of fine particles, while they have a particle size at a level where a problem with fluidity or clinging is less likely to occur (Non-Patent Document 5).
No suitable dosage forms for being delivered to a recipient and delivered to the respiratory system have been found for the compound represented by the formula (I), which exhibits excellent neuraminidase inhibitory activity and is expected to be useful as a drug for treating and preventing influenza virus infections. There has been a demand for the development of a dosage method and a dosage form suitable for delivering the compound to the respiratory tissues.
Existing anti-influenza drugs, which exhibit neuraminidase inhibitory activity similarly to the compound represented by formula (I), include oseltamivir phosphate (trade name: Tamiflu, Patent Document 4) and zanamivir (trade name: Relenza, Patent Document 3). For therapy, these existing drugs have to be repeatedly administered twice daily for five days. If the number of doses can be reduced compared to that of these existing drugs, the dosing convenience can be improved. Due to its property of remaining in virus growth sites such as the lung and other organs for a long time, it is also expected to bring the advantage that, after administration once or twice, virus infection propagation can be inhibited so that secondary damage can be prevented. Thus, there has been a demand for the development of an anti-influenza drug that exhibits neuraminidase inhibitory activity at a level equal to or higher than that of the existing drugs and can be administered using a dosage amount and a dosage frequency which can provide better dosing convenience and better prevention of infection propagation than the existing drugs.